Review ArticleNew Insights on Retrieval-Induced and Ongoing MemoryConsolidation: Lessons from Arc

Jean-Pascal Morin,1,2,3 Kioko Guzmán-Ramos,2,3 and Federico Bermudez-Rattoni2

1 Instituto deNeurobiologıa, UniversidadNacional Autonoma deMexico, Campus Juriquilla, Boulevard Juriquilla 3001, Col. Juriquilla,76230 Santiago de Queretaro, QRO, Mexico2Instituto de Fisiologıa Celular, UNAM, Ciudad Universitaria, 04510 Mexico, DF, Mexico3Departamento de Ciencias de la Salud, Unidad Lerma, Universidad AutonomaMetropolitana (UAM), Avenida de las Garzas No. 10,52005 Lerma, MEX, Mexico

Correspondence should be addressed to Federico Bermudez-Rattoni; fbermude@ifc.unam.mx

Received 15 December 2014; Revised 26 February 2015; Accepted 3 March 2015

Academic Editor: Pedro Bekinschtein

Copyright © 2015 Jean-Pascal Morin et al. This is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properlycited.

The mainstream view on the neurobiological mechanisms underlying memory formation states that memory traces reside on thenetwork of cells activated during initial acquisition that becomes active again upon retrieval (reactivation). These activation andreactivation processes have been called “conjunctive trace.” This process implies that singular molecular events must occur duringacquisition, strengthening the connection between the implicated cells whose synchronous activity must underlie subsequentreactivations. The strongest experimental support for the conjunctive trace model comes from the study of immediate early genessuch as c-fos, zif268, and activity-regulated cytoskeletal-associated protein. The expressions of these genes are reliably induced bybehaviorally relevant neuronal activity and their products often play a central role in long-term memory formation. In this review,we propose that the peculiar characteristics of Arc protein, such as its optimal expression after ongoing experience or familiarbehavior, together with its versatile and central functions in synaptic plasticity could explain how familiarization and recognitionmemories are stored and preserved in the mammalian brain.

1. Introduction: Characterization of IEGs andthe Particularities of Arc

The immediate early genes (IEGs) were first described inviruses and then identified in various cell lines. The IEGs aretranscribed following a variety of stimulations such as growthfactors, hormones, and cytokines in a protein synthesis-independent fashion [1].Their relevance for the study in adultneuronal plasticity was first brought to light in 1987, whenit was shown that c-fos, a protooncogene that is also a tran-scription factor, was rapidly transcribed in neurons followingseizures [2]. A couple of years later, another transcriptionfactor, zif268, was identified; it was expressed after plastic-ity inducing treatments such as maximal electroconvulsiveshocks and long-term potentiation (LTP). It has also beendemonstrated that zif268 transcription is dependent on N-methyl-D-aspartate (NMDA) receptors activity, suggesting

a functional link between these receptors and IEGs inthe process of synaptic plasticity [3, 4]. In the followingyears, Paul Worley and collaborators undertook the task ofidentifying IEGs whose products were directly involved inmodifying cellular function, rather than transcription factorswith a presumably indirect role [5]. This gave rise to thediscovery of a whole new set of “effector” IEGs: the COX-2 [6] an enzyme involved in lipid metabolism that was latershown to be involved in long-term plasticity andmemory [7],Homer1a, a scaffold protein that interacts with metabotropicglutamatergic receptors and modulates intracellular calciumsignaling [8], and activity-regulated cytoskeletal-associatedprotein (Arc), a protein involved in synaptic remodeling andplasticity [9–12]. These IEG products appeared as excellentcandidates for proteins whose ongoing synthesis is essentialfor LTM to occur. However, an obvious intriguing questionremained in how do proteins, newly synthesized in the soma,become associated with potentiated synapses?

Hindawi Publishing CorporationNeural PlasticityVolume 2015, Article ID 184083, 12 pageshttp://dx.doi.org/10.1155/2015/184083

2 Neural Plasticity

In order to explain that question, the concept of “synaptictagging” was introduced. Synaptic tagging is the idea thata translation-independent molecular mark must be estab-lished at potentiated synapses in order to provide inputspecificity for long-term, protein synthesis-dependent plas-ticity mechanisms [13, 14]. With Arc being a candidate forplasticity related proteins recruited by putative synaptic tags,its discovery was particularly encouraging for a number ofreasons. After LTP-inducing stimulation of the perforantpath, Arc mRNAwas shown to accumulate specifically in themedial molecular layer of the dentate gyrus (DG), that is,the dendritic region that received the bulk of the stimulationduring this procedure [15, 16]. Importantly, this phenomenonwas later explained by the dendritic transport of its mRNA,which also was obliterated by NMDA receptors antagonism[15–18].

Further insight on the involvement of Arc in mem-ory formation was gained when researchers examined thedynamics of Arc mRNA in the hippocampal network afterexploration of a novel environment. That is, after 5min ofspatial exploration Arc mRNA was reliably detected in thenuclei of activated cells of the hippocampus and cortex.Interestingly, 25–30 minutes later, the percentage of cellsexpressing Arc mRNA in the nucleus was comparable tothat of control animals, as the transcript already traveledto the cytoplasm where it was reliably detected [19, 20].This kinetics of Arc mRNA combined with the specificityto physiologic stimuli [19, 21] has allowed the design ofa method combining in situ hybridization and confocalmicroscopy to detect large neuronal populations activatedby two or even three distinct behavioral epochs [22, 23].This tool, termed catFISH (for “cellular compartment analysisof temporal activity by fluorescence in situ hybridization”),has helped to advance our understanding of the neuronalcircuit underlying memory storage in a variety of behavioralparadigms. The catFISH technique allowed demonstratingthat the population of cells expressing Arc during a sub-sequent exposure to the same environment highly overlapswith those expressing the mRNA during the first period.However, when the two behavioral epochs consisted in twostrikingly distinct environments, the populations of cellsexpressing Arc were shown to be statistically independent.Noteworthy, in vivo single unit recordings have shown that,during exploratory behavior in rats, ∼18% of CA3 and ∼40%ofCA1 neurons show “place field” activity. Interestingly, it wasdiscovered that a similar proportion of neurons express ArcmRNA in the nucleus.Thus, since these place cells are widelybelieved to store contextually relevant information [24], thisfurther pointed to a role in Arc in declarative memory thatwas consistent with the conjunctive tracemodel. Accordingly,it was demonstrated that acute intrahippocampal inhibitionof Arc translation during the hours following acquisitionimpaired LTMof a spatial navigation task [25]. Amore recentstudy by the same group showed that inactivation of themedial septum, a treatment known to impair hippocampus-dependent learning and memory [26], abolishes behaviorallyinduced Arc expression in this region [27]. Importantlymedial septum inactivation is known to spare locationspecific firing in CA1 place cells [28]. These findings thus

strongly suggest that Arc expressing neurons represent amemory storing engram rather than neuronal activity perse and further strengthen the rationale behind mapping Arcgene expression in neuronal networks during behavior.

Importantly, Arc expression mapping has been helpfulto visualize memory storing neuronal networks not only inthe hippocampus but also in several cortical and subcorticalregions under a wide variety of behavioral paradigms. Forexample, some researchers took advantage of the conditionedtaste aversion (CTA) task in which a strong associativememory is formed even if the conditioned stimulus (a noveltaste) and the unconditioned stimulus (postingestive inducedmalaise) are presented 25min or even more apart [34]. Thisconsiderable time lapse between stimuli allowed the authorsto perform a catFISH design allowing visualization of theconvergence of a conditioned stimulus with the uncondi-tioned stimulus onto single neurons in the basolateral amyg-dala [35]. Indeed, some amygdala neurons were activated byboth stimuli (had both nuclear and cytoplasmic Arc mRNA).However, when the stimuli presentation was reversed, that is,the LiCl injection was first and then the saccharin solutionwas presented after 25min, the proportion of double stainedamygdala neurons was dramatically decreased. These resultsstrongly suggested that the observed convergence in theforward conditioning represented associative learning ratherthan mere overlap in the neuronal response [35]. Later,inspired by this study, another group of researchers used theconditioned odor preference task and showed that neurons ofbasolateral amygdala “learned” to associate an odor with anappetitive taste outcome, as a repeated convergence of tasteand odor inducedArcmRNA increments after several days ofpairing the smell with the taste [36]. A similar phenomenonwas observed in the insular cortex by another group; theyshowed that an odor cue associated with a taste was asefficient at driving IEG expression in insular cortex neuronsas the taste itself [37]. Moreover, in this study it was foundthat when the same taste was presented twice, it tended toinduce IEG transcription (Arc and Homer1a) in the samesubset of neurons in the insular cortex, just as it occurredin the hippocampus after repeated exploration of the sameenvironment [37].

2. Molecular Mechanisms of Arc-DependentSynaptic Plasticity

2.1. Tight Regulation of Arc Expression. As mentioned earlier,intranuclear foci of immature Arc can be detected 2 to 5minafter exposing rats to an open field [19]. If the groups ofneurons that express Arc after information encoding werememory storing networks, one would expect that changesin synaptic activity would play a major role in this fastand discrete Arc expression. Efforts were thus deployed atidentifying the precise cascade of events, from the synapse tothe nucleus, that give rise to Arc expression. A role of putativememory-associated signaling pathways was early suspectedand, accordingly, it was found that depolarization-inducedArc in neurons was dependent on intracellular calciuminflux and activation of cAMP dependent protein kinase andextracellular signal regulated kinase signaling pathways [38].

Neural Plasticity 3

Later, another group showed that glutamate release at exci-tatory synapses induces rapid Arc mRNA transcription inhippocampal neurons by a mechanism that depends onthe transcription factor Myocyte Enhancer Factor type 2activation [39]. However, the effects on Arc expressionobtained in these studies were rather modest consideringthe robust increase observed under physiological conditions[16, 19, 27]. A more recent study further sought to identifyhighly preserved cis-acting elements in the Arc promoterthat could account for the very tight and dramatic activity-dependent increase of Arc transcription reported in earlierstudies. Screening more distal parts of the Arc promoter(∼7 kb) they found a ∼100 bp element that was sufficient toreplicate the full extent of Arc’s activity-dependent induction(∼150 fold increase) after periods of intense activity invitro and coined this element, “synaptic activity responsiveelement” (SARE). Importantly blocking 𝛼-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and NMDAreceptors abolished SARE-induced transcription [40]. Note-worthy, regions within the SARE element matched consen-sus binding sequences for cyclic adenosine monophosphateresponding element binding protein, serum response factor,andMyocyte Enhancer Factor type 2 (CREB, SRF, andMEF2,resp.), three transcription factors strongly involved in neuralplasticity [41].Therefore, this element provided a mechanismby which Arc transcript can be strongly induced, specificallyby synaptic activity.

In addition to the activation of the SARE element, amechanism that ensures rapid synaptic activity-dependentArc transcription was recently unveiled, which resides installed RNA polymerase II at the transcription initiationstarts of Arc promoter [42]. Poised polymerase, along withactive chromatin marks and preloaded transcription factors,provides a mechanism by which an activity induced signalcan bypass the time-consuming process of transcription initi-ation and release RNA polymerase II for active transcription[42]. Interestingly, interfering with RNA polymerase stallingaffected rapid induction of Arc but spared delayed IEG suchas early growth response protein 3. Thus, these new findingson the molecular events that underlie Arc transcription helpto explain how it can exert its function in behaviorallyactivated cells, in a fast and specific manner.

2.2. Arc Localization and Function

2.2.1. Synaptic Strength Decrease. Experiments aimed atuncovering the role of Arc in synaptic plasticity at molecularand cellular levels showed that, in dendritic spines, Arcassociates with the endocytic machinery, interacting withdynamin and endophilin 2/3, components of the clathrin-dependent endocytic machinery, thus enhancing AMPAreceptors endocytosis [43]. Arc is strongly induced in neu-rons where its protein downregulates surface AMPA recep-tors after periods of increased neural activity. Thus activityinduced Arc has a role in homeostatic synaptic scaling [44,45], a non-Hebbian form of plasticity that serves to shiftback neural excitability to physiological range, while preserv-ing the relative change in individual synapses induced byHebbian forms of plasticity, such as LTP [46–48]. Moreover,

rapid dendritic translation of “constitutive” Arc mRNA hasbeen shown to underlie metabotropic glutamate receptors-(mGluR-) dependent long-term depression (LTD) throughArc-dependent AMPA receptors endocytosis [49].

The role of Arc in the cell-wide weakening of glutamater-gic synapses seemed counterintuitive, based on abundantevidence showing accumulation of both Arc mRNA andprotein in potentiated dendritic regions [15, 29], as wellas its requirement for LTP maintenance [25, 50]. However,groundbreaking new evidencewas brought to light in a recentpaper by Hiroyuki Okuno and collaborators that reconciledthe role for Arc in synapse-specific homeostatic plasticityand synaptic tagging [51]. The authors first used a yeasttwo-hybrid screening to identify protein partners binding toArc and identified an interaction with calcium/calmodulin-dependent protein kinase II 𝛽 (CAMKII𝛽). This interactionwas found to be stronger in the absence of the Ca2+/CaMcomplex, suggesting a preferential interaction with the inac-tive form of the kinase. Moreover, after reliably and robustlyinducing global Arc expression in neurons, the authorsexamined the effect of locally suppressing synaptic activity atsingle presynaptic sites. Strikingly, this treatment increasedArc accumulation at the inactivated synapses and, there,Arc was shown to diminish surface AMPA receptor GluR1subunit content. Together, these results show that after peri-ods of increased activity that induce robust Arc expressionin neurons, it specifically accumulates at inactive spines byinteracting with the inactive form of CAMKII𝛽, that is notbound to calmodulin, enabling what was termed “inverse”synaptic tagging. The role of Arc, therefore, appears not onlyto scale down neural excitability after Hebbian synaptic mod-ifications but also to crucially increase the contrast betweenpotentiated and nonpotentiated synapses [52]. As mentionedpreviously, global Arc mRNA increments have consistentlybeen observed at recently activated dendritic regions [22, 29].It is probable that, under the settings used in these studiesand as acknowledged by the authors, LTP occurs only ina subset of the stimulated synapses [29], as is also thoughtto occur during learning [53]. Conceivably, accumulation ofArc mRNA at activated dendrites or dendritic zones couldprovide a mechanism where inactive synapses in the vicinityof recently potentiated ones swiftly recruit massive amountsof Arc protein for synaptic depression to occur at these sites.However, as we shall see in the next section, a wealth of in vivoevidence also argues in favor of a distinct and specific rolefor de novo Arc translation in LTP consolidation at recentlystimulated synapses.

2.2.2. Synaptic Strength Increase. Agrowing body of evidencein favor of a direct role for Arc in synapse strengthening, atleast under certain conditions, has recently received furthersupport. First to be mentioned is that de novo Arc proteinsynthesis was soon shown to be required in vivo for themaintenance phase of LTP of the perforant path [25]. Laterstudies in Arc knockout mice confirmed a role for Arc inboth LTD and LTP. Specifically, LTP induction was shownto be enhanced, while the maintenance phase was abolishedin both perforant path and Schaffer collateral pathways,in agreement with the previous findings [50]. However,

4 Neural Plasticity

the strongest piece of evidence in favor of LTP consolidationappears to come from studies using perforant path stim-ulation of DG’s granule cells. Noteworthy and contrary towhat happens in hippocampal pyramidal cells where bothLTP and novel environment exploration induce a robust andtemporally discrete wave of Arc expression, a more gradualand sustained increase of Arc mRNA and protein appearto be produced by these procedures in DG’s granule cells[33, 54–56]. Importantly, local infusions of Arc asODNs at 2 hfollowing in vivo high frequency stimulation of the perforantpath abolished LTP maintenance and impaired F-actin poly-merization and cofilin phosphorylation, molecular eventsthat are thought to underlie learning-induced structuralplasticity [30, 55, 57].Most strikingly, treatmentwith the actinstabilizing drug jasplakinolide, between LTP induction andArc asODNs treatment, abolished the deleterious effects ofArc translation inhibition on LTPmaintenance.These resultsstrongly suggest that Arc’s role in DG LTP consolidation restsin its ability to stabilize recently polymerized actin filaments[55]. Finally, Arc asODNs infusions before LTP inductionwith high frequency stimulation or BDNF infusions pre-vented LTP expression indicating that Arc translation wasrequired for early LTP expression as well as maintenance.

Recently mechanistically distinct rounds of translationthat depended on sustained MNK activation through BDNFsignaling were shown to underlie DG-LTP [58]. Infusionsof BDNF scavenger TrkB-Fc or MNK inhibition broughtfield evoked postsynaptic potentials as well as Arc proteintranslation back to baseline. All in all, a very strong casecan now be made for a direct role of Arc in DG-LTP. Asobserved before [59, 60] this quite strikingly contrasts withArc’s role in glutamatergic synapses weakening. However,nothing supports the a priori principle that Arc’s functionshould be similar in every studied cell type. In fact, its rolemay differ between pyramidal and granule cells, as it wasrecently proposed for BDNF’s [61]. This possibility shoulddraw serious attention given that, as mentioned earlier, it isnow demonstrated that Arc expression kinetics in granularand pyramidal cells differ dramatically. Further, still littleattention has been paid to possible posttranslational modi-fications to Arc protein as it was observed in an earlier paper[59]. However, possible phosphorylation sites for PKC andCamKII have been identified since the protein’s discovery [9].As pointed out recently, and regardless of the experimentalsettings or cell type, the bulk of Arc protein observed inprincipal activated cell appears in the perinuclear cytoplasm,where its function remains obscure [60] although it is nowestablished that at least part of it is shuttled to the nucleus.

2.2.3. Arc in the Nucleus: Cell-Wide Homeostatic Downscalingof AMPA Receptors. Arc protein was first detected in the cellnucleus of cultured hippocampal neurons in association withpromyelocytic leukemia bodies (PML), which are putativesites of transcriptional regulation [62]. Consistently, a morerecent study further showed that stimulating DG granularcells for prolonged periods, with brain-derived neurotrophicfactor or bicuculline, induced a gradual targeting of Arcto the nucleus that reaches peak levels at 8 h. There, Arcpromotes the assembly of nuclear PMLbodies, which, in turn,

negatively regulate the transcription of the AMPA receptorsubunit GluR1. Importantly also, nuclear localizationwas alsoobserved after exposure to a novel environment not onlyin the granular cells of the DG but also in hippocampalCA1 and CA3 regions and in the somatosensory cortex.Importantly, the kinetics of Arc accumulation to the nucleusvaried depending on the brain region and cell type. Thesefindings thus provide an additional, cell-wide mechanism bywhich Arc promotes homeostatic plasticity, after prolongedperiods of synaptic activity [33]. All in all, Arc accomplishesdistinct functions depending on its interaction partners andthe time course of its accumulation.

2.3. Spine Type-Specific Accumulation of Arc Protein. Anotherinteresting observation is that the Arc-dependent downreg-ulation of surface AMPA receptors appears to be specific tocertain dendritic spines, depending on their morphologicalcharacteristics. Dendritic spines can indeed be classified indistinct categories according to their shape, size, and struc-ture, which are correlated with synaptic strength, motility,and structural plasticity. “Mushroom” spines are larger, aremuch more stable, and have a greater amount of AMPAreceptors than “thin” spines that are also much more labileand dynamic. For these reasons, mushroom spines have beenreferred to as “memory spines,” whereas thin spines are theputative “learning spines” [63]. In agreement, thin spines aremore susceptible to Arc-dependent GluR1 endocytosis [64].Further, Arc knockoutmice have increased seizure sensitivityand epileptiform activity asmeasured with electroencephalo-gram, whereas Arc −/− neurons have decreased spine densitybut, crucially, increased spine width [64]. These findingsconfirmed a role for Arc in homeostatic synaptic scaling andglobal network stability. Arc protein targeting at synapses“tagged” as inactive would diminish unspecific noise andallow nearby potentiated Arc-negative thin spines to standout and eventually become “memory spines.” Conceivably,synaptic potentiation and spine growth could be the “default”mechanism that occurs in behaviorally activated cells; it wellcould be that synaptic inactivity could be the trigger thatconfers specificity. Alternatively, distinct, yet complementary,mechanisms could occur at active synapse that would furtherincrease the contrast between potentiated and unpotentiatedsynaptic networks (see Figure 1).

3. The Requirement of Arc for LTM Formation

Given the synaptic localization ofArc protein, its tight activitydependence, and its striking effects on synaptic function,efforts have been deployed to uncover its possible role atdistinct phases of the process of learning and memory. Thegeneration of Arc knockout mice revealed a role for Arcin long-term but not short-term memory in a variety oftasks, including object recognition memory and amygdala-dependent tasks, such as conditioned taste aversion andfear conditioning, showing that learning per se is unaffectedin these mice [50]. Furthermore, the formation of long-term spatial memory as assessed by Morris Water Mazetask was impaired; Arc knockout mice were slower learners,formed a less precise memory, and, interestingly, showed

Neural Plasticity 5

Novel stimulus

GluR1SARE

Arc transcription

F-actin?Spine growth?

Familiar stimulus

GluR1

Arc transcription

mGluR

SARE

Translation-dependent mRNA

decay

NMDAr

Ribosome

Arc proteinAMPArArc mRNAEJCPML bodies TrkB receptor

Ca2+Ca2+/CaMCaMKII𝛽

mGluR

NMDAr

Ribosome

Arc proteinAMPArArc mRNAEJCPML bodies TrkB receptor

Ca2+Ca2+/CaMCaMKII𝛽

Figure 1: Hypothetical model of the differential role of Arc expression after the presentation of a novel and a familiar stimulus. In bothcases, active Arc expressing cells are presented in which a swift and massive calcium entry through NMDA receptors at synaptic sites inducedramatic increase in Arc mRNA expression through “SARE” activation. Further NMDA receptors activation and increased protein synthesisobserved after novelty exposure could induce synaptic activity and translation-dependent Arc mRNA degradation as it was observed afterDG-LTP [29]. In the novelty condition, increased TrkB activation through BDNF may lead to increase in actin polymerization and spinegrowth at potentiated synapses, mechanisms that, in addition to LTP, are thought to underlie the consolidation of novel information [30]. Onthe other hand, familiarization primes dendrites for mGluR1-LTD and increased Arc protein synthesis [31, 32] arguably after reactivation ofthe same circuit. In addition to synapse-specific downregulation of surface AMPA receptors, a more global, cell-wide mechanism occurs inwhich Arc is shuttled to the nucleus and associates with PML bodies to repress GluR1 transcription. Accumulation of Arc in the nucleus hasbeen observed in the hours following novel environment exploration [33] and may also occur after familiar stimulus exposure.

less behavioral flexibility as they took longer to relearna new position of the target platform [50]. These resultsin the Arc knockout mice were in accordance with theseminal paper of Guzowski and collaborators mentionedearlier that found impaired long-term spatial memory afteracute Arc translation blocking, therefore providing a firstcausal link between de novo Arc protein synthesis and LTMconsolidation [25]. A requirement for de novo Arc proteinexpression for consolidation and reconsolidation processeswas later unveiled in a great variety of learning and memoryparadigms. For example, in the amygdala, a key structureinvolved in the storage of the emotional contingency relatedto a context or a stimulus [65, 66], it was shown that admin-istration of Arc antisense oligodeoxynucleotides (asODNs)before training the animals in a Pavlovian fear conditioningtask affects its consolidation [67]. Furthermore Arc asODNsadministration 90min before reactivation of the same taskin the lateral amygdala impaired reconsolidation of this task[68]. On the other hand, infusions of Arc asODN in thebasolateral amygdala 3 h before extinction of a contextualfear conditioning task impaired shifting of the emotionalcomponent of the context from aversive to safe [69].

Similarly, the importance of de novo Arc translation forLTM formation was also demonstrated in the neocortex,in both associative and nonassociative memory paradigms.For example, posttraining administration of Arc asODNs inthe cingulate cortex was reported to disrupt LTM formationin an inhibitory avoidance paradigm [70]. In our lab, weshowed that inhibiting Arc protein synthesis in the insularcortex prevents familiarization with a safe taste and hindersthe hedonic shifting of a taste from aversive to safe duringextinction of conditioned taste aversion (CTA) (Guzman-Ramos et al., manuscript in preparation). Taken together,these data demonstrate that de novo Arc protein expressionin critical mammalian forebrain structures plays an essentialrole in LTM formation. Therefore, while some factors havebeen identified that specifically operate in either consolida-tion or reconsolidation, this does not seem to be the case ofArc which synthesis appears to be required indistinctively forboth processes [71, 72].These studies indicate that de novoArcprotein synthesis in the participating brain structures seemsto be required for both processes. Furthermore, they are inagreement with observations by ours and other groups show-ing that Arc protein expression increased once a behaviorallyrelevant stimulus becomes familiar (see below).

6 Neural Plasticity

3.1. Is Synergy of Arc-NMDAReceptors Necessary for LTM? Inmany tasks, the requirement for NMDA receptors activity inorder to consolidate LTM has been clearly established [73].A functional link between NMDA receptors activation andIEGs expression has long been suspected to underlie specificsynapticmodifications that are essential for the establishmentof a stable memory trace. As a matter of fact, inhibition ofNMDA receptors is known to hinder activity-dependent ArcmRNA expression, localization at activated dendritic sites,and degradation [9, 15, 29]. However, a direct involvementof Arc-NMDAR interdependency in vivo during learningwas not tested until recently. To this matter, one groupused contextual fear conditioning, a task known to involveNMDA receptors-dependent plasticity mechanisms in thehippocampus [74], and showed an increase in Arc proteinaccumulation in the hippocampus at 1 h after acquisition thatwas blocked by NMDA receptor antagonist APV. Further-more, pretraining infusions of Arc asODNs impaired consol-idation but spared acquisition of contextual fear conditioningtasks [75]. These results clearly point to a role of NMDAreceptors-dependent Arc synthesis in the hippocampus in theformation of a long-term contextual fear memory. Yet a morerecent study sought to determine whether this Arc-NMDAreceptors synergy was also involved in memory retrieval ofa familiar task. Moreover, NMDA receptors activity uponretrieval proved to be essential for contextual memorymaintenance as the increased locomotion upon subsequentcontext exposure was attenuated in rats treated with NMDAreceptors antagonist APV [76]. These findings bring to lightfurther support for the idea that retrieval memories, evenwell-consolidated ones, place the involved circuits in a labilestate that require further NMDA receptors-dependent Arcprotein synthesis for their stabilization. In the next sectionwe will discuss recent findings regarding the phenomenonof retrieval-induced plasticity mechanisms, with a focus onArc, and their possible role in memory stabilization andpersistence.

4. Memory Circuits Reactivations andOngoing Synaptic Plasticity

Hebb’s second postulate stipulated that, in addition to feed-forward synaptic strengthening, reverberation of neuralensembles must occur in order to form a temporary unitof memory storage. These ensembles of neurons facilitatecoincidence detection of upcoming sensorial information byintegrating information from temporally related, but spatiallysegregated, neural activity [77]. In recent years, severallines of experimental evidence have brought support andrefined Hebb’s proposal. In our lab, we examined putativeoffline reactivations after associative learning at the level ofneurochemical extracellular changes, using the conditionedtaste aversion paradigm. First, we found a significant increaseof dopamine levels in the insular cortex during the inges-tion of a novel saccharin solution. Second, intraperitonealinjection of LiCl, used as an unconditioned stimulus in thistask, was shown by itself to produce a swift increment ofglutamate release in this same structure. Strikingly, however,a delayed, concomitant release of dopamine and glutamate

was observed in the insular cortex that was abolished byreversible inactivation of the amygdala, another structureinvolved in long-term conditioned taste aversion memoryformation [78, 79] (interestingly, similar results with the neu-rotransmitters norepinephrine and glutamate were observedin the amygdala [80]). Arguably, the concomitant dopamineand glutamate release we reported in the insular cortex couldprecede and be required for more enduring forms of synapticplasticity in these regions thatwere reported by our group andothers [37, 81, 82].

4.1. Epigenetic Modulation of Arc Expression. Currently, themost widely accepted model accounting for LTM formationstipulates that learning inducesmorphological and functionalmodifications at activated synapses and subsequent learning-dependent protein synthesis allowing stabilization of thesemodifications, so that the newly strengthened synaptic net-works become stored for days to months, a phenomenonthat was termed synaptic consolidation [83]. Recently, anemerging subfield of neuroepigenetics, the study of the roleof epigeneticsmechanisms in adult neurons [84], has recentlyunveiled possible mechanisms by which synapse-specificchanges induced by learning could remain permanently. Inthis regard, the molecular mechanisms of memory main-tenance focused on the cell’s nucleus have been proposed;that is, covalent modifications of the DNA are the ultimatebiochemical event that could store information permanently[85]. Notably, this phenomenon could work in parallel withwider distribution of the memory trace through corticalnetworks in order to further stabilize memories. The conceptof epigenetics refers to “changes in gene transcription throughmodulation of chromatin, which are not brought by changesin DNA sequence” [86].There are two possible ways in whichthese modulations of chromatin could play a role in memorystorage. On one hand, stable chromatin modifications caninterdigitate with synaptic tags in order to participate inand maintain synapse-specific changes [87]. Another possi-bility could be that neuroepigenetic mechanisms since theyoperate at a cell-wide level could induce metaplasticity inselected populations of neurons so that the tuning up ordown of specific synapses would be permanently facilitated[87]. Importantly, epigenetic modifications at promoter sitesof various plasticity related proteins, including Arc, haverecently been described [88, 89].

As mentioned earlier Arc-dependent AMPA receptorsendocytosis operates both at a synapses specific level, throughsynaptic inactivity-dependent interaction with CAMKII𝛽[51, 52], and in a cell-wide fashion, through downregulationof GluR1 transcription [33]. Interestingly, methylation of theArc promoter that correlated in time with a decrease in Arcprotein below basal levels has been reported at 24 h afterthe induction of electroconvulsive seizures [90]. Also, aber-rant changes in Arc promoter methylation in hippocampalneurons have been suggested to play a role in age-relatedcognitive decline [91]. Methylation, a putative gene silencingsignal, is arguably the most stable epigenetic modificationand could serve to maintain changes in gene expressiondynamics induced by memory consolidation [92]. Indeedmethylation of memory suppressing gene calcineurin was

Neural Plasticity 7

induced in the frontal cortex after contextual fear condition-ing and persisted for at least 30 days. Further, interferingwith the enzymes responsible for maintaining methylationon cytosine residues, on the 30th day after conditioning,significantly impaired retention of the task [92]. On theother hand, knocking-down of Tet1, an enzyme that promotesDNA demethylation, is associated with decreased expressionof synaptic plasticity related, putative memory enhancergenes Nasp4, c-fos, Egr2, and Arc as well as abnormallyenhanced LTD and impaired memory extinction [93]. Thissuggests that the methylation rate of these genes affects theeffectiveness of subsequent plasticity inducing events, thusmodulating their ability to update consolidated memoriesupon reactivation. Taken together, these findings providecrucial insights on the role of chromatin modifications inlong-term memory persistence and will undoubtedly set thebasis for important new discoveries in this field, in the yearsto come. Meanwhile, they might also provide a “rationale”behind the robust Arc and other plasticity related proteins’expression that is observed after retrieval of even “well-consolidated”memories, as well as during offline rest periods.

5. Familiar/Consolidated Tasks InduceRobust Arc Expression: Abundant Evidencebut Still Elusive Function

Some characteristics of Arc expression during ongoingbehavioral experience, especially at the posttranscriptionallevel, are somewhat counterintuitive, given its role inmemoryconsolidation. In fact undermany setups it has been observedthat Arc mRNA and protein are still expressed at high levelsafter the animal experiences an already familiarized contextor stimulus. Further, under some circumstances, exposure toa familiar behavioral stimulation induces even greater Arcexpression. In a recent study exploringArcmRNAexpressiondynamics in hippocampal subfields after running around atrack in a novel context, optimal Arc expressionwas observedin CA3 after a rat ran around a track a single time; no furtherincrement was observed when the animal ran several timesaround the same track or when it ran several times for fourconsecutive days. In CA1, on the other hand, the greaterproportion of Arc expressing cells was observed in the condi-tion where the animal ran several times around the track forthe fourth consecutive day in the same context [27]. First ofall, these data provided compelling support at the molecularlevel for a role of CA3 in the fast encoding and subsequentstorage of a novel context. Further, it provided evidence thatbehaviorally induced plasticity mechanisms are still requiredin the hippocampus even when the environment is familiar[27] and is consistent with earlier studies that found robustspatial exploration-induced Arc mRNA expression in DGgranular cells even after the environment was experienced forthe ninth time [94]. Also in agreement with these findings,it was reported by the same group that Arc transcription inrats trained in the Morris Water Maze task is similar afterovertraining compared to after initial acquisition [95]. Allthese findings suggest that active spatial exploration induceArc-dependent plasticity mechanisms in the hippocampusevery time it is reinstated, regardless of familiarity [95].

Strong evidence links LTD, that is, a decrease in theefficiency of synaptic communication, with the formationof object recognition memory, and recent evidence pointsto a role for Arc for this type of recognition memory. Forexample, exploration of a novel object has been associ-ated with induction of LTD in CA1 network, since novelobject exploration during low-frequency stimulation of theSchaffer-collateral pathway facilitated LTD in rats [31, 96].Recently, it was shown that exposure to a novel environ-ment induced strong dendritic expression of Arc mRNAin hippocampal CA1 pyramidal neurons, but translationremained tightly repressed. However, further exposure tothe same environment lifted the break on Arc translation inthe dendrite and allowed AMPA receptor-dependent LTD toproceed [97]. Therefore, an attractive possibility suggested inthe same study could be that recognition memory operatesin such a way that novelty primes activated neurons forLTDbutArc translation remains temporally suppressed, untilsubsequent experienceswith the familiarized stimulus triggerArc translation locally at the dendrite and, therefore, promotelong-lasting depression, allowing a sparser memory trace tobe established.

Parallel lines of evidence suggest that a similar mecha-nism could be involved under different sensorial modalities.Seeking to elucidate Arc expression dynamics in neocorticalnetworks, a recent work analyzed how a previous exposureto a sound affects Arc mRNA expression in the auditorycortex after presentation of the same sound on the follow-ing day. The same proportion of neurons expressed ArcmRNA after rats were presented with the sound, whetherit was novel or familiar. However, they detected a greaterproportion of cells with Arc transcript in the cytoplasmspecifically after exposure to the familiar sound [32]. Theseresults provide compelling evidence that a single exposureto a noncontingent stimulus could modulate Arc expressiondynamics in cortical networks and provide further evidencethat Arc-dependent plasticity mechanisms are still occur-ring during behavioral familiarity. In our lab, we soughtto evaluate Arc protein expression dynamics during tasterecognition memory formation. We unexpectedly found thatfamiliar saccharin consumption induced higher Arc proteinaccumulation in the insular cortex than novel saccharin,even when the amount of fluid consumed remained constantbetween the two conditions. Strikingly, local infusion ofanisomycin in the dorsal hippocampus, a treatment knownto affect taste familiarization [79], prevented the increase ofArc protein in the insular cortex observed on the secondday. Further, immunofluorescence analysis revealed that thegreater presence of Arc in the familiar condition was due toa dramatic increase in dendritic accumulation of the proteinand that the same proportion of cells expressed Arc after bothnovel and familiar taste [98].

The fact that high levels of Arc protein expression arestill observed even after the execution of a familiarized taskcould well be explained by memory consolidation-inducedepigenetic changes that promote a shift in the transcriptionalresponse of a given circuit upon subsequent reactivations.Also, it has been proposed that this sustained Arc expressionafter ongoing experience could serve to maintain the trace

8 Neural Plasticity

in a labile state in order to enable subsequent updatingof the memory trace [27]. Consistently, extinction of anin vitro classical conditioning task induces similar synapticlevels of Arc protein more than initial acquisition does [99].Moreover, recent findings from our lab have shown thatde novo Arc protein synthesis in the insular cortex uponaversive taste memory retrieval is essential for aversive-to-positive hedonic shift of the taste valence (Guzman-Ramos,Venkataraman, Morin, and Bermudez-Rattoni, manuscriptin preparation). However, the key question is whether Arcsynthesis is required in asymptotically learned tasks, whenno additional information or further updating is involved.Experiments from our lab found that optimal dendritic Arcprotein expression occurred when the taste was presentedfor the fifth time, that is, when behavioral assessment oftaste familiarization (Attenuation of Neophobia [34]) sug-gests that it is indeed asymptotically familiarized. Further,as mentioned earlier, other groups have found that Arcprotein expression occurs in a similar proportion of cells afterexploration of a novel and a familiarized environment [95].These results indicate that de novo Arc protein is requiredevery time a familiarizationmemory is reactivated, nomatterhow consolidated it is; however, no clear loss of functionstudy has addressed this issue. Furthermore, most of Arcknockdown experiments have used asODNs, which onlyinhibit a fraction of Arc translation and are relatively unstableand subject to degradationmitigating their effects.The recentdevelopment of more stable asODNs, as well as in vivo virus-mediated knockdown experiments, could help address thisquestion with more precision.

Finally, in addition to plasticity mechanisms induced bymemory reactivation, ongoing synaptic modifications mustoccur offline in order to keep the memory trace stable. Inkeeping with this, it was discovered that offline wave ofArc protein expression in hippocampal networks occurredat 8 h and 24 h after spatial exploration [56]. In the DG, onthe other hand, a single 5 min spatial exploration task wasshown to produce sustained transcription of Arc mRNA ingranular cells for as long as 8 hours [54]. Furthermore, it wasshown that “basal” Arc mRNA expression in CA1 neuronsduring rest periods is not random but rather recapitulatesprevious experiences [100]. Importantly, it was shown that thefraction of neurons expressing Arc after spatial explorationand expressing it again during a subsequent rest period ishighest in CA3 and lowest in the cortex [101], which is inaccordance with the systems consolidation theory.

Here again, as a possible explanation for these so-calledoffline genomic reactivations, an epigenetic event, such asDNAmethylation, could occur during initial acquisition andserve as an indelible footprint that allows for a subsequentround of synapse-specific consolidation to be accomplishedevery time the same network is solicited. Such an epigenetictag could also alter the rate or susceptibility of transcription ofcertain genes in an ongoing fashion, in the absence of stimuli.In the future, more extensive characterization of learning-induced epigenetic modifications of Arc and other memory-related genes at specific loci will in our view greatly refine ourunderstanding of how memories are dynamically stored andmaintained over the range of years.

6. Conclusions and Further Issues

This review examined new findings on the role of Arc inlong-term synaptic plasticity and memory formation. As wehave seen, Arc’s unique role in altering network function,possibly as a synaptic contrast enhancer, is reflected bythe wide range of brain structures and memory paradigmsin which its synthesis is required for LTM formation toproceed. Also particularly intriguing are the several modelsin which its translation is optimally promoted by stimulusfamiliarity rather than novelty or retrieval of a consolidatedmemory rather than establishment of a novel one. Furtherinformation on Arc’s regulation mechanisms, particularly atthe epigenetic level and on its molecular partners at thesynapse should provide helpful insights for the emerging fieldof the neurobiological basis of memory persistence.

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper.

Acknowledgments

The authors would like to thank Martha L. Escobar forhelpful comments on an earlier version of this paper. Jean-Pascal Morin is supported by a postdoctoral fellowshipfrom the Programa de Becas de Estancias Postdoctorales(Doctorado en Ciencias Biologicas y de la Salud) at Universi-dadAutonomaMetropolitana. Federico Bermudez-Rattoni issupported by Grants DGAPA-UNAM IN209413 and CONA-CYT.

References

[1] H. Okuno, “Regulation and function of immediate-early genesin the brain: beyond neuronal activity markers,” NeuroscienceResearch, vol. 69, no. 3, pp. 175–186, 2011.

[2] J. I.Morgan,D. R.Cohen, J. L.Hempstead, andT.Curran, “Map-ping patterns of c-fos expression in the central nervous systemafter seizure,” Science, vol. 237, no. 4811, pp. 192–197, 1987.

[3] A. J. Cole, D. W. Saffen, J. M. Baraban, and P. F. Worley, “Rapidincrease of an immediate early gene messenger RNA in hip-pocampal neurons by synaptic NMDA receptor activation,”Nature, vol. 340, no. 6233, pp. 474–476, 1989.

[4] P. F. Worley, R. V. Bhat, J. M. Baraban, C. A. Erickson, B. L.McNaughton, and C. A. Barnes, “Thresholds for synaptic acti-vation of transcription factors in hippocampus: correlationwithlong-term enhancement,” Journal of Neuroscience, vol. 13, no. 11,pp. 4776–4786, 1993.

[5] A. Lanahan and P.Worley, “Immediate-early genes and synapticfunction,” Neurobiology of Learning and Memory, vol. 70, no. 1-2, pp. 37–43, 1998.

[6] K. Yamagata, K. I. Andreasson, W. E. Kaufmann, C. A. Barnes,and P. F. Worley, “Expression of a mitogen-inducible cyclooxy-genase in brain neurons: regulation by synaptic activity andglucocorticoids,” Neuron, vol. 11, no. 2, pp. 371–386, 1993.

[7] T. R. Cowley, B. Fahey, and S. M. O’Mara, “COX-2, but notCOX-1, activity is necessary for the induction of perforant path

Neural Plasticity 9

long-term potentiation and spatial learning in vivo,” EuropeanJournal of Neuroscience, vol. 27, no. 11, pp. 2999–3008, 2008.

[8] J. C. Tu, B. Xiao, J. P. Yuan et al., “Homer binds a novel proline-rich motif and links group I metabotropic glutamate receptorswith IP3 receptors,” Neuron, vol. 21, no. 4, pp. 717–726, 1998.

[9] G. L. Lyford, K. Yamagata,W. E. Kaufmann et al., “Arc, a growthfactor and activity-regulated gene, encodes a novel cyto-skeleton-associated protein that is enriched in neuronal den-drites,” Neuron, vol. 14, no. 2, pp. 433–445, 1995.

[10] E. Korb and S. Finkbeiner, “Arc in synaptic plasticity: from geneto behavior,”Trends in Neurosciences, vol. 34, no. 11, pp. 591–598,2011.

[11] C. R. Bramham, M. N. Alme, M. Bittins et al., “The Arc ofsynaptic memory,” Experimental Brain Research, vol. 200, no. 2,pp. 125–140, 2010.

[12] J. D. Shepherd and M. F. Bear, “New views of Arc, a masterregulator of synaptic plasticity,”Nature Neuroscience, vol. 14, no.3, pp. 279–284, 2011.

[13] U. Frey and R. G. M. Morris, “Synaptic tagging and long-termpotentiation,” Nature, vol. 385, no. 6616, pp. 533–536, 1997.

[14] U. Frey and R. G. M. Morris, “Synaptic tagging: implicationsfor late maintenance of hippocampal long-term potentiation,”Trends in Neurosciences, vol. 21, no. 5, pp. 181–188, 1998.

[15] O. Steward and P. F. Worley, “Selective targeting of newlysynthesized Arc mRNA to active synapses requires NMDAreceptor activation,” Neuron, vol. 30, no. 1, pp. 227–240, 2001.

[16] O. Steward, C. S.Wallace, G. L. Lyford, and P. F.Worley, “Synap-tic activation causes the mRNA for the IEG Arc to localizeselectively near activated postsynaptic sites on dendrites,” Neu-ron, vol. 21, no. 4, pp. 741–751, 1998.

[17] C. S. Wallace, G. L. Lyford, P. F. Worley, and O. Steward,“Differential intracellular sorting of immediate early genemRNAs depends on signals in the mRNA sequence,” Journal ofNeuroscience, vol. 18, no. 1, pp. 26–35, 1998.

[18] J. L. Dynes and O. Steward, “Dynamics of bidirectional trans-port of Arc mRNA in neuronal dendrites,” Journal of Compara-tive Neurology, vol. 500, no. 3, pp. 433–447, 2007.

[19] J. F. Guzowski, B. L.McNaughton, C. A. Barnes, and P. F.Worley,“Environment-specific expression of the immediate-early geneArc in hippocampal neuronal ensembles,”Nature Neuroscience,vol. 2, no. 12, pp. 1120–1124, 1999.

[20] A. Vazdarjanova, B. L. McNaughton, C. A. Barnes, P. F. Worley,and J. F. Guzowski, “Experience-dependent coincident expres-sion of the effector immediate-early genes Arc and Homer 1a inhippocampal and neocortical neuronal networks,” The Journalof Neuroscience, vol. 22, no. 23, pp. 10067–10071, 2002.

[21] J. F. Guzowski, B. Setlow, E. K. Wagner, and J. L. McGaugh,“Experience-dependent gene expression in the rat hippocampuafter spatial learning: a comparison of the immediate-earlygenes Arc, c-fos, and zif268,” Journal of Neuroscience, vol. 21, no.14, pp. 5089–5098, 2001.

[22] J. F. Guzowski, B. L.McNaughton, C. A. Barnes, and P. F.Worley,“Imaging neural activity with temporal and cellular resolutionusing FISH,” Current Opinion in Neurobiology, vol. 11, no. 5, pp.579–584, 2001.

[23] J. F. Guzowski and P. F. Worley, “Cellular compartment anal-ysis of temporal activity by fluorescence in situ hybridization(catFISH),”Current Protocols in Neuroscience, chapter 1: unit 1.8,2001.

[24] D. M. Smith and S. J. Y. Mizumori, “Hippocampal place cells,context, and episodic memory,”Hippocampus, vol. 16, no. 9, pp.716–729, 2006.

[25] J. F. Guzowski, G. L. Lyford, G. D. Stevenson et al., “Inhibitionof activity-dependent arc protein expression in the rat hip-pocampus impairs the maintenance of long-term potentiationand the consolidation of long-term memory,” The Journal ofNeuroscience, vol. 20, no. 11, pp. 3993–4001, 2000.

[26] M. P. McDonald, T. C. Gleason, J. K. Robinson, and J. N. Craw-ley, “Galanin inhibits performance on rodent memory tasks,”Annals of the New York Academy of Sciences, vol. 863, pp. 305–322, 1998.

[27] T. Miyashita, S. Kubik, N. Haghighi, O. Steward, and J. F.Guzowski, “Rapid activation of plasticity-associated gene tran-scription in hippocampal neurons provides a mechanism forencoding of one-trial experience,” Journal of Neuroscience, vol.29, no. 4, pp. 898–906, 2009.

[28] S. J. Y. Mizumori,Hippocampal Place Fields: Relevance to Learn-ing and Memory Hippocampal Place Fields Represent Integrated,Experience—Dependent Sensory and Behavioral Information,2008.

[29] S. Farris, G. Lewandowski, C. D. Cox, andO. Steward, “Selectivelocalization of Arc mRNA in dendrites involves activity- andtranslation-dependent mRNA degradation,” The Journal ofNeuroscience, vol. 34, no. 13, pp. 4481–4493, 2014.

[30] P. Caroni, A. Chowdhury, and M. Lahr, “Synapse rearrange-ments upon learning: from divergent-sparse connectivity todedicated sub-circuits,” Trends in Neurosciences, vol. 37, no. 10,pp. 604–614, 2014.

[31] A. Kemp and D. Manahan-Vaughan, “Hippocampal long-termdepression and long-term potentiation encode different aspectsof novelty accquisition,” Proceedings of the National Academy ofSciences of the United States of America, vol. 101, no. 21, pp. 8192–8197, 2004.

[32] T. N. Ivanova, A. Matthews, C. Gross et al., “Arc/Arg3.1 mRNAexpression reveals a subcellular trace of prior sound exposurein adult primary auditory cortex,”Neuroscience, vol. 181, pp. 117–126, 2011.

[33] E. Korb, C. L. Wilkinson, R. N. Delgado, K. L. Lovero, and S.Finkbeiner, “Arc in the nucleus regulates PML-dependentGluA1 transcription and homeostatic plasticity,” Nature Neuro-science, vol. 16, no. 7, pp. 874–883, 2013.

[34] F. Bermudez-Rattoni, “Molecular mechanisms of taste-reco-gnition memory,”Nature Reviews Neuroscience, vol. 5, no. 3, pp.209–217, 2004.

[35] S. K. Barot, Y. Kyono, E.W. Clark, and I. L. Bernstein, “Visualiz-ing stimulus convergence in amygdala neurons during associa-tive learning,” Proceedings of the National Academy of Sciencesof theUnited States of America, vol. 105, no. 52, pp. 20959–20963,2008.

[36] B. Desgranges, V. Ramirez-Amaya, I. Ricano-Cornejo, F. Levy,and G. Ferreira, “Flavor preference learning increases olfactoryand gustatory convergence onto single neurons in the basolat-eral amygdala but not in the insular cortex in rats,” PLoS ONE,vol. 5, no. 4, Article ID e10097, 2010.

[37] M. P. Saddoris, P. C. Holland, and M. Gallagher, “Associa-tively learned representations of taste outcomes activate taste-encoding neural ensembles in gustatory cortex,”The Journal ofNeuroscience, vol. 29, no. 49, pp. 15386–15396, 2009.

10 Neural Plasticity

[38] R. Waltereit, B. Dammermann, P. Wulff et al., “Arg3.1/ArcmRNA induction by Ca2+ and cAMP requires protein kinasea and mitogen-activated protein kinase/extracellular regulatedkinase activation,” Journal of Neuroscience, vol. 21, no. 15, pp.5484–5493, 2001.

[39] S.W. Flavell, C.W. Cowan, T.-K. Kim et al., “Activity-dependentregulation of MEF2 transcription factors suppresses excitatorysynapse number,” Science, vol. 311, no. 5763, pp. 1008–1012, 2006.

[40] T. Kawashima, H. Okuno, M. Nonaka et al., “Synaptic activity-responsive element in the Arc/Arg3.1 promoter essential forsynapse-to-nucleus signaling in activated neurons,” Proceedingsof the National Academy of Sciences of the United States ofAmerica, vol. 106, no. 1, pp. 316–321, 2009.

[41] S. W. Flavell and M. E. Greenberg, “Signaling mechanismslinking neuronal activity to gene expression and plasticity of thenervous system,” Annual Review of Neuroscience, vol. 31, pp.563–590, 2008.

[42] R. N. Saha, E. M. Wissink, E. R. Bailey et al., “Rapid activity-induced transcription of Arc and other IEGs relies on poisedRNApolymerase II,”NatureNeuroscience, vol. 14, no. 7, pp. 848–856, 2011.

[43] S. Chowdhury, J. D. Shepherd, H. Okuno et al., “Arc/Arg3.1interacts with the endocytic machinery to regulate AMPAreceptor trafficking,” Neuron, vol. 52, no. 3, pp. 445–459, 2006.

[44] E. M. Rial Verde, J. Lee-Osbourne, P. F. Worley, R. Malinow,and H. T. Cline, “Increased expression of the immediate-early gene arc/arg3.1 reducesAMPAreceptor-mediated synaptictransmission,” Neuron, vol. 52, no. 3, pp. 461–474, 2006.

[45] J. D. Shepherd, G. Rumbaugh, J. Wu et al., “Arc/Arg3.1 mediateshomeostatic synaptic scaling of AMPA receptors,” Neuron, vol.52, no. 3, pp. 475–484, 2006.

[46] G. W. Davis, “Homeostatic control of neural activity: fromphenomenology to molecular design,” Annual Review of Neu-roscience, vol. 29, pp. 307–323, 2006.

[47] S. B. Nelson and G. G. Turrigiano, “Strength through diversity,”Neuron, vol. 60, no. 3, pp. 477–482, 2008.

[48] G. G. Turrigiano, “The self-tuning neuron: synaptic scaling ofexcitatory synapses,” Cell, vol. 135, no. 3, pp. 422–435, 2008.

[49] M. W. Waung, B. E. Pfeiffer, E. D. Nosyreva, J. A. Ronesi, andK. M. Huber, “Rapid translation of Arc/Arg3.1 selectively medi-ates mGluR-dependent LTD through persistent increases inAMPAR endocytosis rate,” Neuron, vol. 59, no. 1, pp. 84–97,2008.

[50] N. Plath,O.Ohana, B.Dammermann et al., “Arc/Arg3.1 is essen-tial for the consolidation of synaptic plasticity and memories,”Neuron, vol. 52, no. 3, pp. 437–444, 2006.

[51] H. Okuno, K. Akashi, Y. Ishii et al., “Inverse synaptic taggingof inactive synapses via dynamic interaction of Arc/Arg3.1 withCaMKII𝛽,” Cell, vol. 149, no. 4, pp. 886–898, 2012.

[52] R. Kim, H. Okuno, and H. Bito, “Deciphering the molecularrules governing synaptic targeting of the memory-related pro-tein Arc,” Communicative and Integrative Biology, vol. 5, no. 5,pp. 496–498, 2012.

[53] J. R. Whitlock, A. J. Heynen, M. G. Shuler, and M. F. Bear,“Learning induces long-termpotentiation in the hippocampus,”Science, vol. 313, no. 5790, pp. 1093–1097, 2006.

[54] V. Ramirez-Amaya, A. Angulo-Perkins, M. K. Chawla, C. A.Barnes, and S. Rosi, “Sustained transcription of the immediate

early gene Arc in the dentate gyrus after spatial exploration,”Journal of Neuroscience, vol. 33, no. 4, pp. 1631–1639, 2013.

[55] E. Messaoudi, T. Kanhema, J. Soule et al., “Sustained Arc/Arg3.1synthesis controls long-termpotentiation consolidation throughregulation of local actin polymerization in the dentate gyrus invivo,” Journal of Neuroscience, vol. 27, no. 39, pp. 10445–10455,2007.

[56] V. Ramırez-Amaya, A. Vazdarjanova, D. Mikhael, S. Rosi, P.F. Worley, and C. A. Barnes, “Spatial exploration-induced ArcmRNA and protein expression: evidence for selective, network-specific reactivation,” Journal of Neuroscience, vol. 25, no. 7, pp.1761–1768, 2005.

[57] M. Bosch, J. Castro, T. Saneyoshi, H. Matsuno, M. Sur, andY. Hayashi, “Structural and molecular remodeling of dendriticspine substructures during long-term potentiation,” Neuron,vol. 82, no. 2, pp. 444–459, 2014.

[58] D. Panja, J. W. Kenney, L. D’Andrea et al., “Two-stage transla-tional control of dentate gyrus LTP consolidation is mediatedby sustained BDNF-TrkB signaling to MNK,” Cell Reports, vol.9, no. 4, pp. 1430–1445, 2014.

[59] C. R. Bramham, P. F. Worley, M. J. Moore, and J. F. Guzowski,“The immediate early geneArc/Arg3.1: regulation,mechanisms,and function,” The Journal of Neuroscience, vol. 28, no. 46, pp.11760–11767, 2008.

[60] O. Steward, S. Farris, P. S. Pirbhoy, J. Darnell, and S. J. van Dri-esche, “Localization and local translation of Arc/Arg3.1 mRNAat synapses: some observations and paradoxes,” Frontiers inMolecular Neuroscience, vol. 7, article 101, 2015.

[61] D. Panja and C. R. Bramham, “BDNF mechanisms in late LTPformation: a synthesis and breakdown,” Neuropharmacology,vol. 76, pp. 664–676, 2014.

[62] W. A. C. Bloomer, H. M. A. VanDongen, and A. M. J. VanDon-gen, “Activity-regulated cytoskeleton-associated protein Arc/Arg3.1 binds to spectrin and associates with nuclear promye-locytic leukemia (PML) bodies,” Brain Research, vol. 1153, no. 1,pp. 20–33, 2007.

[63] J. Bourne and K. M. Harris, “Do thin spines learn to be mush-room spines that remember?”Current Opinion in Neurobiology,vol. 17, no. 3, pp. 381–386, 2007.

[64] C. L. Peebles, J. Yoo, M. T. Thwin, J. J. Palop, J. L. Noebels, andS. Finkbeiner, “Arc regulates spine morphology and maintainsnetwork stability in vivo,” Proceedings of the National Academyof Sciences of the United States of America, vol. 107, no. 42, pp.18173–18178, 2010.

[65] T. Sigurdsson, V. Doyere, C. K. Cain, and J. E. LeDoux, “Long-term potentiation in the amygdala: a cellular mechanism of fearlearning and memory,” Neuropharmacology, vol. 52, no. 1, pp.215–227, 2007.

[66] J. LeDouxe, “Primer: the amygdala,” Current Biology, vol. 17, no.20, pp. R868–R874, 2007.

[67] J. E. Ploski, V. J. Pierre, J. Smucny et al., “The activity-regulatedcytoskeletal-associated protein (Arc/Arg3.1) is required formemory consolidation of pavlovian fear conditioning in thelateral amygdala,” Journal of Neuroscience, vol. 28, no. 47, pp.12383–12395, 2008.

[68] S. A. Maddox and G. E. Schafe, “The activity-regulated cyto-skeletal-associated protein (Arc/Arg3.1) is required for recon-solidation of a pavlovian fear memory,” The Journal of Neuro-science, vol. 31, no. 19, pp. 7073–7082, 2011.

Neural Plasticity 11

[69] K. Onoue, D. Nakayama, Y. Ikegaya, N. Matsuki, and H.Nomura, “Fear extinction requires Arc/Arg3.1 expression in thebasolateral amygdala,” Molecular Brain, vol. 7, no. 1, article 30,2014.

[70] C. M. Holloway and C. K. McIntyre, “Post-training disruptionof Arc protein expression in the anterior cingulate corteximpairs long-term memory for inhibitory avoidance training,”Neurobiology of Learning and Memory, vol. 95, no. 4, pp. 425–432, 2011.

[71] B. Bozon, S. Davis, and S. Laroche, “A requirement for theimmediate early gene zif268 in reconsolidation of recognitionmemory after retrieval,” Neuron, vol. 40, no. 4, pp. 695–701,2003.

[72] Y. Dudai, “The restless engram: consolidations never end,”Annual Review of Neuroscience, vol. 35, pp. 227–247, 2012.

[73] S.-H. Wang and R. G. M. Morris, “Hippocampal-neocorticalinteractions in memory formation, consolidation, and recon-solidation,”Annual Review of Psychology, vol. 61, pp. 49–79, C1–4, 2010.

[74] J. J. Quinn, F. Loya, Q. D. Ma, and M. S. Fanselow, “Dorsalhippocampus NMDA receptors differentially mediate trace andcontextual fear conditioning,” Hippocampus, vol. 15, no. 5, pp.665–674, 2005.

[75] J. Czerniawski, F. Ree, C. Chia, K. Ramamoorthi, Y. Kumata, andT. A. Otto, “The importance of having arc: expression ofthe immediate-early gene arc is required for hippocampus-dependent fear conditioning and blocked by NMDA receptorantagonism,” The Journal of Neuroscience, vol. 31, no. 31, pp.11200–11207, 2011.

[76] Y.Alaghband, S. J. O’Dell, S. Azarnia, A. J. Khalaj, J. F. Guzowski,and J. F. Marshall, “Retrieval-induced NMDA receptor-dependent Arc expression in two models of cocaine-cuememor,” Neurobiology of Learning and Memory, vol. 116, pp.79–89, 2014.

[77] D. O. Hebb,TheOrganization of Behavior: A NeuropsychologicalTheory, Psychology Press, New York, NY, USA, 1949.

[78] K. Guzman-Ramos, D. Osorio-Gomez, P. Moreno-Castilla,and F. Bermudez-Rattoni, “Off-line concomitant release ofdopamine and glutamate involvement in taste memory consol-idation,” Journal of Neurochemistry, vol. 114, no. 1, pp. 226–236,2010.

[79] V. de la Cruz, C. J. Rodriguez-Ortiz, I. Balderas, and F.Bermudez-Rattoni, “Medial temporal lobe structures partici-pate differentially in consolidation of safe and aversive tastememories,” European Journal of Neuroscience, vol. 28, no. 7, pp.1377–1381, 2008.

[80] K. Guzman-Ramos, D. Osorio-Gomez, P. Moreno-Castilla, andF. Bermudez-Rattoni, “Post-acquisition release of glutamateand norepinephrine in the amygdala is involved in taste-aversion memory consolidation,” Learning & Memory, vol. 19,no. 6, pp. 231–238, 2012.

[81] L. Nunez-Jaramillo, L. Ramırez-Lugo,W. Herrera-Morales, andM. I. Miranda, “Taste memory formation: latest advances andchallenges,” Behavioural Brain Research, vol. 207, no. 2, pp. 232–248, 2010.

[82] F. Bermudez-Rattoni, “The forgotten insular cortex: its role onrecognition memory formation,” Neurobiology of Learning andMemory, vol. 109, pp. 207–216, 2014.

[83] Y. Dudai, “The neurobiology of consolidations, or, how stable isthe engram?” Annual Review of Psychology, vol. 55, pp. 51–86,2004.

[84] J. J. Day and J. D. Sweatt, “DNA methylation and memoryformation,” Nature Neuroscience, vol. 13, no. 11, pp. 1319–1323,2010.

[85] F. Crick, “Memory and molecular turnover,” Nature, vol. 312,article 101, 1984.

[86] M.Wood, “Introduction to the special issue of Neurobiology ofLearning andMemory on epigenetics and memory,”Neurobiol-ogy of Learning and Memory, vol. 96, no. 1, 2011.

[87] J. D. Sweatt, “The emerging field of neuroepigenetics,” Neuron,vol. 80, no. 3, pp. 624–632, 2013.

[88] J. J. Day and J. D. Sweatt, “Cognitive neuroepigenetics: a role forepigenetic mechanisms in learning and memory,” Neurobiologyof Learning and Memory, vol. 96, no. 1, pp. 2–12, 2011.

[89] M. R. Penner, T. L. Roth, C. A. Barnes, and J. D. Sweatt, “Anepigenetic hypothesis of aging-related cognitive dysfunction,”Frontiers in Aging Neuroscience, vol. 2, article 9, 2010.

[90] M. Dyrvig, H. H. Hansen, S. H. Christiansen, D. P. D. Woldbye,J. D. Mikkelsen, and J. Lichota, “Epigenetic regulation of Arcand c-Fos in the hippocampus after acute electroconvulsivestimulation in the rat,” Brain Research Bulletin, vol. 88, no. 5,pp. 507–513, 2012.

[91] M. R. Penner, T. L. Roth, M. K. Chawla et al., “Age-relatedchanges in Arc transcription and DNA methylation within thehippocampus,” Neurobiology of Aging, vol. 32, no. 12, pp. 2198–2210, 2011.

[92] C.A.Miller, C. F.Gavin, J. A.White et al., “CorticalDNAmethy-lation maintains remote memory,” Nature Neuroscience, vol. 13,no. 6, pp. 664–666, 2010.

[93] A. Rudenko, M. Dawlaty, J. Seo et al., “Tet1 is critical for neu-ronal activity-regulated gene expression and memory extinc-tion,” Neuron, vol. 79, no. 6, pp. 1109–1122, 2013.

[94] M. K. Chawla, J. F. Guzowski, V. Ramirez-Amaya et al., “Sparse,environmentally selective expression of Arc RNA in the upperblade of the rodent fascia dentata by brief spatial experience,”Hippocampus, vol. 15, no. 5, pp. 579–586, 2005.

[95] T. Miyashita, S. Kubik, G. Lewandowski, and J. F. Guzowski,“Networks of neurons, networks of genes: an integrated view ofmemory consolidation,”Neurobiology of Learning andMemory,vol. 89, no. 3, pp. 269–284, 2008.

[96] D. Manahan-Vaughan and K.-H. Braunewell, “Novelty acqui-sition is associated with induction of hippocampal long-termdepression,” Proceedings of the National Academy of Sciences ofthe United States of America, vol. 96, no. 15, pp. 8739–8744, 1999.

[97] V. Jakkamsetti, N.-P. Tsai, C. Gross et al., “Experience-inducedArc/Arg3.1 primes CA1 pyramidal neurons for metabotropicglutamate receptor-dependent long-term synaptic depression,”Neuron, vol. 80, no. 1, pp. 72–79, 2013.

[98] J.-P.Morin, C. Quiroz, L.Mendoza-Viveros, V. Ramirez-Amaya,and F. Bermudez-Rattoni, “Familiar taste induces higher den-dritic levels of activity-regulated cytoskeleton-associated pro-tein in the insular cortex than a novel one,” Learning andMemory, vol. 18, no. 10, pp. 610–616, 2011.

[99] J. Keifer, Z. Zheng, and M. Mokin, “Synaptic localizationof GluR4-containing AMPARs and Arc during acquisition,extinction, and reacquisition of in vitro classical conditioning,”

12 Neural Plasticity

Neurobiology of Learning and Memory, vol. 90, no. 2, pp. 301–308, 2008.

[100] D. F. Marrone, M. J. Schaner, B. L. McNaughton, P. F. Worley,andC.A. Barnes, “Immediate-early gene expression at rest reca-pitulates recent experience,” The Journal of Neuroscience, vol.28, no. 5, pp. 1030–1033, 2008.

[101] A. Gheidi, E. Satvat, and D. F.Marrone, “Experience-dependentrecruitment of Arc expression in multiple systems during rest,”Journal of Neuroscience Research, vol. 90, no. 9, pp. 1820–1829,2012.

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